Selective RET Inhibitors Research Articles

Role of RET and BRAF genes in thyroid cancer with relevance in gene therapy treatment

At present, cancer is a global problem, among all the types that exist, one of those that was taken into account for this research is thyroid cancer, especially associated with the predisposing genes of RET rearrangement and BRAF gene mutation, which incite the rapid exit of papillary thyroid carcinoma, from MAPK signaling pathways and conformational change by mutation in BRAF at position (V600E) and (V599E). The aim of the subsequent study is to provide recent information on the genes involved, as well as the potential impact of targeted therapies to inhibit these pathways, such as selective RET and BRAF inhibitors, providing a strategy for gene therapy and rather than the traditional approach of thyroidectomy. In addition to the way of its diagnosis by means of different genetic markers, oncogenic genes, genome sequence and generalized findings of the endocrine-genetic problem. This research also explores non-specific associations of the above-mentioned causes, generating a broader knowledge for future medical and genetic adaptation of the disease.

Is peptide receptor radionuclide therapy still a promising option for medullary thyroid carcinoma?

Medullary thyroid carcinoma (MTC) is a rare cancer that originates from germline RET proto-oncogene mutations in all hereditary forms and from somatic RET mutations in most sporadic cases. Currently, highly selective RET inhibitors have been approved for clinical use in patients with RET mutations with persistent, recurrent or metastatic disease. This therapy has proven efficacy, low toxicity, and a limited impact on patients' quality of life. However, for recurrent or metastatic RET-negative disease, few systemic therapies are available. Multikinase inhibitors are used; however, tumour cells frequently develop resistance mechanisms, or treatment must be discontinued due to the high incidence of side effects. In this context, peptide receptor radionuclide therapy (PRRT) may be a treatment option, but its clinical utility remains under investigation. The aim of this review is to evaluate the evidence of PRRT in MTC and discuss its limitations in the RET inhibitor era.

Efficacy and safety of RET-TKI in advanced RET-rearranged non-small cell lung cancer in China: areal-worldretrospective chart review.

Selective RET inhibitors have been approved by the Chinese government for the treatment of RET-rearranged non-small cell lung cancer. This study aimed to illustrate the efficacy and safety of selective RET inhibitors in a real-world clinical context in China. Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring RET rearrangement and receiving RET tyrosine kinase inhibitors (RET-TKI) in the real world were enrolled in this retrospective study. Clinical data, including baseline clinicopathological information, efficacy parameters such as objective response rate (ORR) and progression-free survival (PFS), and adverse events (AEs), were collected from the electronic medical record system. The pattern of treatment failure of first-line RET-TKI was also described. Fifty-one patients were enrolled in this study. RET-TKI induced an ORR of 73.1% and a median PFS (mPFS) of 22.7months (95%CI, 11.7-33.7) in the first-line setting. The ORR and mPFS were 58.3% and 17.7months (95%CI, 9.1-26.2), 55.6% and 14.7months (95%CI, 12.6-16.8) in the second-line and later-line settings, respectively. No significant difference was observed among different application lines with respect to the ORR (P = 0.534) or PFS (P = 0.795). In the first-line setting, RET-TKI significantly prolonged PFS compared to other regimens including chemotherapy-based regimens, multikinase inhibitors and other systemic regimens without chemotherapy (P < 0.05). Poor ECOG performance status was related to shorter PFS (P = 0.018). The most common AEs of grade 3 or worse were a decreased neutrophil count (11.4%) and anemia (11.4%). No new AEs or grade 5 AEs were observed. Brain metastasis was one of the most common patterns of treatment failure. In patients with baseline brain metastasis, the intracranial ORR was 50%, and the DCR was 100%. RET-TKI had favorable efficacy and safety in real-world contexts in China and should be considered the preferred choice for first-line treatment in RET-rearranged NSCLC patients.

Real-World Outcomes of Selective RET Inhibitor Selpercatinib in the United States: Descriptive, Retrospective Findings from Two Databases.

This study described real-world patient characteristics and outcomes among selpercatinib-treated patients in the United States, using the Flatiron Health electronic health record-derived deidentified database (FHD) for advanced/metastatic non-small cell lung cancer (a/mNSCLC) and Optum's de-identified Clinformatics® Data Mart Database (CDM). Patients initiating selpercatinib treatment between 08MAY2020 and 30JUN2023 were included. We evaluated real-world time to selpercatinib treatment discontinuation or death (rwTTDd) and time to next treatment or death (rwTTNTd) using Kaplan-Meier analyses. Medication possession ratio (MPR) was estimated as a measure of medication adherence in CDM patients. In a/mNSCLC patients from the FHD (N = 68), the median rwTTDd and rwTTNTd were 22.4 [95%CI: 13.3-NR] and 21.0 [95%CI: 11.6-NR] months, respectively. In CDM, these durations were 12.1 [95%CI: 9.6-NR] and 16.2 [95%CI: 9.6-NR] months for lung cancer (n = 43), while these were not reached for thyroid cancer (n = 24) patients. The median MPR was 0.98 [IQR: 0.84-1.00] among all patients in the CDM (N = 75), with 77.3% of patients adhering (MPR ≥ 0.80) to selpercatinib. Real-world outcomes in this older and frailer patient cohort align with phase 3 trial results, further supporting selpercatinib as the standard of care for patients with RET-altered cancers. Early testing for the detection of RET alterations remains essential.

First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors

Oncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).

98 (PB086): First-in-human, phase 1 study of a selective RET inhibitor, LOXO-260, in patients with RET inhibitor refractory, RET-altered cancers

98 (PB086): First-in-human, phase 1 study of a selective RET inhibitor, LOXO-260, in patients with RET inhibitor refractory, RET-altered cancers

1295P EP0031 a next-generation selective RET inhibitor (SRI): Correlation of molecular and clinical responses in patients with RET alteration positive solid tumours naïve to or following prior SRI

1295P EP0031 a next-generation selective RET inhibitor (SRI): Correlation of molecular and clinical responses in patients with RET alteration positive solid tumours naïve to or following prior SRI

Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: "Shadows and Fogs".

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1-2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the 'old' multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.

Efficacy and safety of 1L selpercatinib in RET fusion-positive NSCLC: LIBRETTO-431 East Asian subgroup analysis.

214 Background: In prior studies, the efficacy and safety of selpercatinib, a selective RET inhibitor, was consistent in RET+ NSCLC pts across geographies. As previously reported, LIBRETTO-431 met its primary endpoint of improved PFS by blinded independent central review (BICR) at the pre-planned interim analysis. Here we report the efficacy and safety from LIBRETTO-431 in pts from East Asia, a majority of the study population. Methods: LIBRETTO-431 (NCT04194944) is a randomized, open-label phase 3 trial comparing 1L selpercatinib vs control (platinum/pemetrexed +/- pembrolizumab). Geography (East Asia vs non-East Asia) was a stratification factor. BICR-assessed PFS, ORR and DOR were examined in pts from East Asia randomized with investigator’s intent to treat with pembrolizumab (ITT-pembro) if assigned to control. AE data were collected for all pts from East Asia who received at least one dose of selpercatinib or control (n=140). Results: Of 142 randomized pts from East Asia, 116 were included in the ITT-pembro population (selpercatinib: n=75, control: n=41). Baseline characteristics were well balanced, however the selpercatinib arm had slightly more pts from East Asia vs the control arm (58% vs 49%). In ITT-pembro pts from East Asia, with a median follow up of 19.4 mo and 21.2 mo in the selpercatinib and control arms respectively, the median PFS was not yet reached with selpercatinib (95% CI: 16.4-NE) vs 11.1 mo (95% CI: 7.0-16.8) with control. At 12 mo the PFS rate was 72.8% with selpercatinib vs. 41.7% with control. The ORR was 86.7% (95% CI: 76.8-93.4) with selpercatinib vs 61.0% (95% CI: 44.5-75.8) with control. Similar results were observed in pts from East Asia in the overall ITT population. The most common AEs reported in pts from East Asia on selpercatinib included elevated AST (73.6%), elevated ALT (70.3%), hypertension (60.4%), increased blood bilirubin (52.7%) and diarrhea (44.0%) while those reported with control included anemia (61.2%), elevated AST (49.0%), leukopenia (49.0%), neutropenia (44.9%) and elevated ALT (42.9%). A summary of safety data for selpercatinib vs control in pts from East Asia is presented in the table. Conclusions: LIBRETTO-431 is the first randomized study to report efficacy and safety of a RET inhibitor in pts from East Asia. Consistent with the results in the overall population, selpercatinib demonstrated superior PFS compared to chemotherapy + pembrolizumab in 1L pts from East Asia. These data support early comprehensive genomic testing and the use of selpercatinib as the preferred 1L regimen in RET+ NSCLC pts across geographies. Clinical trial information: NCT04194944 . [Table: see text]

LIBRETTO-432: A phase 3 study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive (RET+) NSCLC.

TPS216 Background: Around 30% of NSCLC patients (pts) present with stage IB-IIIA disease. Standard treatment options are definitive locoregional therapies w/wo chemotherapy (CT) and/or immunotherapy, followed by surveillance until disease recurrence. Targeted therapies are standard for metastatic NSCLC with driver alterations and recent Phase III trial data has emerged in support of their use in the adjuvant setting for stage IB-IIIA (ADAURA and ALINA). RET is a key oncogenic driver in NSCLC and a promising target for adjuvant targeted therapy. Selpercatinib, a highly selective, potent and CNS active RET inhibitor, recently demonstrated longer PFS than platinum-based CT as 1L treatment in pts with RET+ advanced NSCLC (Zhou et al. NEJM 2023). LIBRETTO-432 is a Phase 3, global, multicenter, randomized, double-blind, controlled trial evaluating efficacy and safety of adjuvant selpercatinib v Placebo in pts with RET+ Stage IB-IIIA NSCLC following completion of definitive therapies with curative intent, and other adjuvant therapy if indicated (NCT04819100). Methods: Pts (n≈170) will be randomized (1:1) to selpercatinib BID [160mg ≥50kg; 120mg &lt;50kg], or Placebo, in continuous 28-day cycles for a maximum treatment duration of 3y. Stratification factors include disease stage (IB/II/IIIA) and prior definitive therapy. Treatment will continue until disease recurrence/progression, unacceptable toxicity, or another protocol-defined reason. Crossover is allowed for Placebo pts who experience disease recurrence/progression. Key eligibility criteria include age ≥18 y; histologically confirmed Stage IB/II/IIIA NSCLC; RET+ tumor by PCR/NGS; prior definitive locoregional therapy with curative intent (surgery, radiotherapy) for Stage IB/II/IIIA NSCLC; and ECOG performance status 0-1. Maximum time allowed from definitive therapy completion to randomization is 26 w. Key exclusion criteria are evidence of other known oncogenic drivers; SCLC; and disease recurrence/progression following definitive therapy. Primary endpoint is investigator-assessed event-free survival (IAEFS) in the primary analysis population (pts with Stage II-IIIA). EFS is defined as time from randomization until locoregional disease recurrence with histopathological confirmation, distant disease recurrence per RECIST v1.1 or histopathological confirmation, or death. Gated secondary endpoints include IAEFS in the overall population (pts with Stage IB-IIIA) and OS in both primary analysis and overall populations. Non-gated secondary efficacy endpoints include BICR-assessed EFS, BICR and investigator-assessed time to distant disease recurrence in the CNS, and PFS on next line of treatment. Recruitment is ongoing, with enrollment across ~170 sites and 30 countries. Results from this trial will further inform the value of RET inhibition and genomic testing for adjuvant NSCLC pts. Clinical trial information: NCT04819100 .

Intracranial outcomes of 1L selpercatinib in advanced RET fusion-positive NSCLC: LIBRETTO-431 study.

199 Background: Selpercatinib is a highly selective and potent CNS active RET inhibitor approved for treatment of advanced RET fusion-positive ( RET+) NSCLC. Treatment or prevention of CNS disease is critical in RET+ NSCLC patients (pts), who have nearly a 50% lifetime prevalence of brain metastases (mets) (Drilon et al. JTO 2018). LIBRETTO-431 is the first study to compare intracranial (IC) efficacy of a targeted therapy to chemo/IO in pts with oncogene driven NSCLC. Methods: LIBRETTO-431 (NCT04194944) is a randomized, open-label, phase 3 trial comparing 1L selpercatinib vs chemotherapy (cisplatin/carboplatin + pemetrexed) +/- pembrolizumab. As previously reported, the study met its primary endpoint of PFS by blinded independent central review (BICR) at the pre-planned interim analysis. IC analyses included CNS and non-CNS PD, IC PFS and IC responses by BICR per RECIST 1.1 in all pts who had a baseline and one or more post-baseline CNS scans (CNS-evaluable) and were designated to receive pembrolizumab if randomized to the control arm (CNS-pembro population). Adverse events were evaluated in the CNS safety population. Results: A total of 192 of 261 pts enrolled were CNS-evaluable (selpercatinib: 120, control: 72). Baseline characteristics were generally balanced with the selpercatinib arm having a slightly lower proportion of pts with BICR-assessed baseline brain mets (21% vs 25%) and prior CNS radiotherapy (RT; 6% vs 10%) compared to the control arm. Selpercatinib delayed CNS PD as evidenced by a lower 12 mo cumulative incidence rate (CIR) for CNS PD, as well as delaying non-CNS PD compared to control in pts with and without brain mets (Table). In pts with measurable brain mets at baseline (n=29), median time to IC response per RECIST 1.1 was similar between selpercatinib and control (1.4 mo [range: 1.2-2.9] vs 1.6 mo [range: 1.2-2.9]); however, as previously reported the IC response rates were higher (82% vs 58%) and more durable (12 mo DOR rate 76% vs 63%) with selpercatinib vs control (Zhou et al. NEJM 2023). IC responses to selpercatinib were more common in pts without prior CNS RT (14/15, 93%) than with prior CNS RT (3/6, 50%). Conclusions: Selpercatinib delayed IC progression in advanced RET+ NSCLC pts with or without baseline brain mets and achieved higher IC response rates compared to chemotherapy + pembrolizumab. LIBRETTO-431 is the first study to demonstrate IC efficacy improvement of a targeted therapy vs chemo/IO in a biomarker selected NSCLC population. These data further support selpercatinib as the preferred 1L regimen in pts with advanced RET+ NSCLC. Clinical trial information: NCT04194944 . [Table: see text]

Rapid response to selpercatinib in RET fusion positive pancreatic neuroendocrine carcinoma confirmed by smartwatch

This case report describes the efficacy of selpercatinib, a selective RET inhibitor, in an unusual case of large-cell neuroendocrine pancreatic carcinoma (LCNEPAC) harboring a CCDC6::RET fusion. A 56-year-old male with a history of multiple lines of systemic therapies exhibited marked clinical amelioration shortly after initiating selpercatinib within the LOXO-RET-17001 study (ClinicalTrials.gov ID: NCT03157128, first posted: 2017-05-17). Data from the patient’s smartwatch suggested early efficacy before conventional methods, such as serum tumor markers and CT imaging confirmed the antitumor activity. This case not only underscores the efficacy of selpercatinib in treating RET fusion-positive rare tumors but also highlights the potential of wearable technology in cancer care. In conclusion, the standard readings from commercially available wearable devices can be useful for the monitoring of treatment response to targeted therapy and may serve as digital biomarkers in clinical trials. This approach marks a significant advancement in patient-centric healthcare, leveraging technology to enhance the effectiveness and precision of treatment evaluation.

Thyroid carcinomas: the role of systemic therapies in internal medicine

The molecular pathogenesis of thyroid carcinoma is well studied and of importance for the treatment of advanced stages. Differentiated, poorly differentiated and anaplastic carcinomas originate in the follicular cells, while medullary carcinomas derive from the C‑cells. The prognosis of differentiated thyroid carcinoma is generally very favourable after surgery and radioiodine therapy. Where tumours progress and lose the ability to enrich iodine, curative treatment is usually not possible. Astrategy of watchful waiting is often appropriate. Activating mutations in BRAF or gene fusions of RET and NTRK provide opportunities for targeted therapies. These may be applied with the aim of restoring iodine uptake (redifferentiation). In the absence of molecular therapy targets, multityrosine kinase inhibitors (MKI) are the therapy of choice. If anaplastic thyroid carcinoma is suspected, rapid diagnostic workup including molecular pathology is warranted. Surgery where possible and radiochemotherapy are essential components of therapy. In the presence of aBRAF mutation, inhibition of BRAF and MEK is effective, even if it is not approved in Germany. Where molecular targets are lacking, combination therapy with the MKI lenvatinib and immune checkpoint inhibition is highly effective. Mutations in RET are present in the vast majority of cases of medullary thyroid carcinoma. In aggressive advanced disease, selective RET inhibition has recently been approved as first-line therapy and often leads to an objective response and long-lasting disease stabilisation. In summary, thyroid carcinomas are among the tumour entities for which molecularly targeted therapies can be used most frequently. The involvement of specialised centres is advisable.

Acute severe hypocalcaemia after initiation of a selective ret inhibitor in medullary thyroid cancer

Acute severe hypocalcaemia after initiation of a selective ret inhibitor in medullary thyroid cancer

Efficacy and safety of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET-fusion positive non-small cell lung cancer (NSCLC): Results from a multicenter, single-arm, phase II study.

Efficacy and safety of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced<i> RET</i>-fusion positive non-small cell lung cancer (NSCLC): Results from a multicenter, single-arm, phase II study.

Safety and efficacy of selpercatinib in pediatric patients with RET-altered solid tumors: Updated results from LIBRETTO-121.

10022 Background: Selpercatinib is a highly selective and potent CNS-penetrant oral RET inhibitor, approved for treatment of RET-driven thyroid cancer in adult and adolescent patients (pts), and lung or other solid tumors in adult pts. Here we present updated results from LIBRETTO-121, the first trial to assess the safety and efficacy of a selective RET inhibitor in pediatric and adolescent pts with RET-altered solid tumors. Methods: LIBRETTO-121 (NCT03899792) is a multicenter phase 1/2 trial in pts 0.5-21 yrs of age with advanced, RET-altered solid tumors. Enrollment began in June 2019 and is ongoing. To confirm the recommended phase 2 dose for selpercatinib, dosing started at 92 mg/m2 BID, expecting to result in equivalent exposure to 160 mg BID in adults.The primary objectives were to evaluate safety and dose limiting toxicities (DLTs) in phase 1 and determine the ORR per RECIST 1.1 by independent review in the phase 2 population. Results: At the data cut-off (January 13, 2023), 27 pts aged 2-20 yrs were treated with selpercatinib. Tumor types included RET-mutant medullary thyroid cancer (MTC, n = 14), RET fusion-positive papillary thyroid cancer (PTC, n = 10), or other (n = 3). The most common RET alterations were a M918T mutation (71.4% [10/14] of MTC pts) or NCOA4-RET fusion (50% [5/10] of PTC pts). Pediatric and adolescent patients treated at 92 mg/m2 (up to 160 mg BID) had a similar exposure as adults treated with 160 mg BID at steady state on cycle 1 day 8. Time on selpercatinib ranged from 0.4 to 40.8 mo and 22 pts remain on treatment. There were no treatment discontinuations due to DLTs or TEAEs; 2 pts (7.4%) experienced a dose reduction due to TEAEs (elevated ALT and reduced neutrophil count). The most common TEAEs observed (≥25% of pts) were diarrhea, headache, coronavirus infection, nausea, vomiting, elevated ALT, elevated AST and pyrexia. The most common TEAEs ≥ G3 included constipation, reduced neutrophil count, vomiting and weight gain, each occurring in 2 pts (7.4%). One pt (age 15 yrs) experienced a TEAE ≥ G3 of epiphysiolysis, a risk for selpercatinib in this population based on pre-clinical data. In pts with RECIST measurable disease at baseline, the ORR was 83.3% (10/12), while 1 pt had stable disease (SD) and 1 pt had progressive disease (PD). Among pts with measurable disease at baseline, PTC pts had an ORR of 100% (5/5), and MTC pts had an ORR of 83.3% (5/6), while 1 MTC pt had SD. No PTC or MTC pts had PD. Responses were durable, with a 24 mo DOR rate of 100% (95% CI: NE, NE). With a median follow up of 18 mo, the mPFS among all pts has not yet been reached, and the 24 mo rate of PFS was 92.4% (95% CI: 73.0% - 98.1%). Conclusions: Selpercatinib’s safety profile remains consistent with prior reports from adult trials. These results, including more robust efficacy and PK data, continue to support the use of selpercatinib in pediatric and adolescent pts with RET-altered solid tumors. Clinical trial information: NCT03899792 .

A phase-1 dose escalation and expansion study of EP0031, a next-generation selective RET inhibitor (SRI), in patients with SRI-naïve or pretreated advanced RET-altered NSCLC and other tumors.

A phase-1 dose escalation and expansion study of EP0031, a next-generation selective RET inhibitor (SRI), in patients with SRI-naïve or pretreated advanced RET-altered NSCLC and other tumors.

LIBRETTO-432: A phase 3 study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive (RET+) NSCLC.

TPS8115 Background: Around 30% of NSCLC patients (pts) present with stage IB-IIIA disease. Standard treatment options are definitive locoregional therapies w/wo chemotherapy (CT) and/or immunotherapy, followed by surveillance until disease recurrence. Targeted therapies are standard for metastatic NSCLC with driver alterations and recent Phase III trial data has emerged in support of their use in the adjuvant setting for stage IB-IIIA (ADAURA and ALINA). RET is a key oncogenic driver in NSCLC and a promising target for adjuvant targeted therapy. Selpercatinib, a highly selective, potent and CNS active RET inhibitor, recently demonstrated longer PFS than platinum-based CT as 1L treatment in pts with RET+ advanced NSCLC (Zhou et al. NEJM 2023). LIBRETTO-432 is a Phase 3, global, multicenter, randomized, double-blind, controlled trial evaluating efficacy and safety of adjuvant selpercatinib v Placebo in pts with RET+ Stage IB-IIIA NSCLC following completion of definitive therapies with curative intent, and other adjuvant therapy if indicated (NCT04819100). Methods: Pts (n≈170) will be randomized (1:1) to selpercatinib BID [160mg ≥50kg; 120mg &lt; 50kg], or Placebo, in continuous 28-day cycles for a maximum treatment duration of 3y. Stratification factors include disease stage (IB/II/IIIA) and prior definitive therapy. Treatment will continue until disease recurrence/progression, unacceptable toxicity, or another protocol-defined reason. Crossover is allowed for Placebo pts who experience disease recurrence/progression. Key eligibility criteria include age ≥18 y; histologically confirmed Stage IB/II/IIIA NSCLC; RET+ tumor by PCR/NGS; prior definitive locoregional therapy with curative intent (surgery, radiotherapy) for Stage IB/II/IIIA NSCLC; and ECOG performance status 0-1. Maximum time allowed from definitive therapy completion to randomization is 26 w. Key exclusion criteria are evidence of other known oncogenic drivers; SCLC; and disease recurrence/progression following definitive therapy. Primary endpoint is investigator-assessed event-free survival (IAEFS) in the primary analysis population (pts with Stage II-IIIA). EFS is defined as time from randomization until locoregional disease recurrence with histopathological confirmation, distant disease recurrence per RECIST v1.1 or histopathological confirmation, or death. Gated secondary endpoints include IAEFS in the overall population (pts with Stage IB-IIIA) and OS in both primary analysis and overall populations. Non-gated secondary efficacy endpoints include BICR-assessed EFS, BICR and investigator-assessed time to distant disease recurrence in the CNS, and PFS on next line of treatment. Recruitment is ongoing, with enrollment across ~170 sites and 30 countries. Results from this trial will further inform the value of RET inhibition and genomic testing for adjuvant NSCLC pts. Clinical trial information: NCT04819100 .

Health-related quality of life (HRQoL) and symptoms in LIBRETTO-431 patients with RET fusion-positive advanced non-small-cell lung cancer (NSCLC).

11068 Background: LIBRETTO-431 (NCT04194944), a randomized phase 3 trial, compared first-line selpercatinib to platinum-based chemotherapy +/- pembrolizumab (pembro). Selpercatinib, a highly selective and potent CNS penetrant RET inhibitor, is approved for the treatment of advanced RET fusion+ NSCLC. This analysis reported NSCLC symptoms and HRQoL from LIBRETTO-431. Methods: This analysis used data (cut-off date: May 01, 2023) from the intent-to-treat (ITT) pembro subpopulation [selpercatinib (n=129); chemotherapy + pembro (control, n=83)] to assess time to confirmed deterioration (TTCD) of NSCLC symptoms (cough, dyspnea, pain, fatigue, poor appetite using NSCLC-Symptom Assessment Questionnaire [SAQ]). TTCD of NSCLC symptoms were defined as time from randomization to the first score that met the pre-specified meaningful within-patient change thresholds, confirmed at next assessment. TTCD was compared between treatment arms using log-rank test and Cox proportional hazards model. Changes of NSCLC-SAQ total score (meaningful important difference [MID] ≥2 points) and HRQoL (using EORTC QLQ-C30 Physical Function (MID ≥6 points) and Global Health Status (GHS)/QoL (MID ≥5 points)) up to 1 year were evaluated and compared between the arms using a growth curve model and mixed model for repeated measures. Results: Selpercatinib significantly (p &lt;.05) delayed TTCD of all individual symptoms with hazard ratio ranging from 0.41 (cough and pain) to 0.57 (dyspnea), compared to control (Table). Selpercatinib also showed a significant and clinically meaningful difference in the mean NSCLC-SAQ total score (difference = -2.0, p &lt;.001) and physical function (difference = 8.1, p =.003) at 1 year, compared to control. GHS/QoL was improved in both arms with no difference in the mean scores between the arms at 1 year. Conclusions: Selpercatinib significantly delayed TTCD of NSCLC symptoms and improved physical function compared to control in this patient population after 1 year of treatment. The findings were consistent with the favorable efficacy of selpercatinib compared with platinum-based chemotherapy + pembro and further support 1L use of selpercatinib in this population. [Table: see text]

Discovery of 9H-pyrimido[4,5-b]indole derivatives as dual RET/TRKA inhibitors

Aberrant RET kinase signaling is activated in numerous cancers including lung, thyroid, breast, pancreatic, and prostate. Recent approvals of selective RET inhibitors, pralsetinib and selpercatinib, has shifted the focus of RET kinase drug discovery programs towards the development of selective inhibitors. However, selective inhibitors invariably lose efficacy as the selective nature of the inhibitor places Darwinian-like pressure on the tumor to bypass treatment through the selection of novel oncogenic drivers. Further, selective inhibitors are restricted for use in tumors with specific genetic backgrounds that do not encompass diverse patient classes. Here we report the identification of a pyrimido indole RET inhibitor found to also have activity against TRK. This selective dual RET/TRK inhibitor can be utilized in tumors with both RET and TRK genetic backgrounds and can also provide blockade of NTRK-fusions that are selected for from RET inhibitor treatments. Efforts towards developing dual RET/TRK inhibitors can be beneficial in terms of encompassing more diverse patient classes while also achieving blockade against emerging resistance mechanisms.